Collateral circulation is a fundamental component of stroke pathophysiology that has been relatively unexplored. The principal objective of this study is to characterize the nature of collateral circulation in acute ischemic stroke and to evaluate augmentation of oxygen status via collaterals as a therapeutic strategy for acute cerebral ischemia. The Specific Aims are 1) to establish a standard angiographic rating scale of leptomeningeal collaterals in acute middle cerebral artery (MCA) stroke, 2) to determine accurate MRI correlates of leptomeningeal collateral circulation, 3) to develop a novel physiologic measure for the adequacy of retrograde leptomeningeal collateral blood flow - oxygen sampling of arterial blood distal to MCA occlusion - and employ this measure to investigate the presence and reversibility of deoxygenation in collateral-derived arterial blood, and 4) to demonstrate that endovascular, intracarotid administration of aqueous oxygen to enhance oxygen delivery via leptomeningeal collaterals in patients with acute MCA ischemia is feasible, safe, and potentially efficacious. These Aims will be addressed in a prospective, nonrandomized, single-center, feasibility, safety, and exploratory efficacy study of endovascular aqueous oxygen delivery in 44 patients within 8 hours of onset of acute ischemic stroke due to MCA occlusion. The rationale for this study is that therapeutic augmentation of oxygen content in leptomeningeal collaterals may diminish ischemia and improve microcirculatory perfusion. Comprehensive angiographic evaluation of collaterals combined with multimodal MRI and oxygen sampling will considerably enhance our current understanding of collateral circulation in acute ischemic stroke. Dynamic aspects of collateral recruitment or collateral failure will be chronicled with serial MRI, including diffusion-perfusion sequences and MRA. As a K23 proposal, this Award will also support a detailed program of didactic coursework and mentored interactive training in clinical research, neuroimaging, and cerebral fluid mechanics, designed to enable the candidate to become a fully independent and productive investigator in patient-oriented cerebrovascular research. The proposed study will lay the foundation for a future era of collateral therapeutics, providing tools and approaches for the evaluation of a wide range of emerging collateral enhancement strategies.